Uno rose through the ranks of the Shooto mixed martial arts organization in Japan. In May 1999, Uno fought the then-legendary Rumina Sato. The fight was hailed as "Fight of the Year", an extremely fast-paced back and forth battle with a wide variety of stand-up and grappling exchanges.[citation needed] Eventually, Uno took the back of Sato and choked him into submission.

The two rematched in December 2000. This fight concluded with Uno throwing Sato on his back, then striking him with a combination of kicks and punches, eventually knocking him out.

After his second victory over Rumina Sato, Uno was recruited to fight for the UFC's Bantamweight (later renamed Lightweight) title against Jens Pulver. Throughout the fight, Pulver stopped Uno's takedown attempts and pressed the action on the feet. Uno, who had earned a reputation as being "unflappable", began to show frustration for the first time in his career as Pulver neutralized all his offensive efforts.[citation needed] Pulver took a majority decision win in the fight.

After Pulver left the UFC, the Lightweight Championship was vacated. A tournament was put together pitting the top Lightweights in the UFC (B.J. Penn, Din Thomas, Matt Serra and Caol Uno). In the first round, Uno faced Thomas. Thomas dominated the first round, setting a high pace. However, Uno turned things around, taking the second and third rounds to win the fight.

In the finals of the tournament, Uno faced Penn (who had previously defeated Uno by knockout in under 12 seconds). Uno used angles and effective wrestling techniques to frustrate Penn, who appeared tentative from the start, while Penn was dominant in spurts. The fight was called a draw and neither fighter won the championship belt.

Uno then went on to fight Tatsuya Kawajiri in Shooto before fighting at K-1's 2004 Premium Dynamite!! and K-1 MAX: Japan Grand Prix 2005. His next eleven fights were for the then newly established promotion Hero's.

Uno was spotted in attendance at UFC 94, fueling talk of a return to the UFC's Lightweight division. It was later confirmed that Uno had signed with the UFC and would face Spencer Fisher at UFC 99: The Comeback, which Uno lost by unanimous decision. Then, on November 21, 2009, Uno fought UFC newcomer Fabrício Camões to a majority draw at UFC 106.

On March 31, 2010, Uno fought Gleison Tibau at UFC Fight Night 21. He was overpowered by the much bigger Tibau, and suffered a loss via TKO (punches).[4] After the fight he was released from the promotion.